This is the second revision of a proposal entitled "Tuberous Sclerosis Complex in Memory Formation". Elucidation of the molecular events underlying the formation and storage of memory is not only relevant for understanding information processing in the brain but also for the development of therapies to treat memory disorders. Memory formation is initiated by neurotransmitters and neurotrophic factors released as a result of neuronal activity during the learning experience. Engaged neurotrophic receptors activate three key intracellular signaling cascades: Ras-Erk, PLCgamma and PI3-kinase. Although the PLCgamma and Ras- Erk pathways have been extensively examined in long-term spatial memory formation, the role of the equally important PI3K cascade in memory formation has received less attention. Recent genetic and biochemical experiments show that tuberous sclerosis protein -2 (TSC2) is phosphorylated by AKT, a key protein kinase activated by PI3K. The TSC1-TSC2 complex regulates the activity of the mammalian target for rapamycin (mTOR), which increases translation of specific mRNA through its action on ribosomal S6 kinase (S6K, also called p70s6k) and/or 4EBP1 (4E binding protein 1). The dominant role of mTOR in PI3K signaling is evident from experimental findings demonstrating that tumors caused by constitutive activation of the PI3K cascade can be targeted by rapamycin, a highly selective inhibitor for mTOR. In addition to its regulation by AKT phosphorylation, the TSC-mTOR pathway is regulated by adenosine monophosphate-activated kinase (AMPK) which acts as an energy sensor for the cell. In this proposal, we will examine in Specific Aim 1: if the TSC-mTOR pathway is activated following training and is required for spatial memory storage in the hippocampus, in Specific Aim 2: if the memory enhancing effect of glucose is in part acting through the TSC- mTOR pathway in the hippocampus, and in Specific Aim 3: if conditional tsc2 (-/-) mice have impaired spatial memory, and if these impairments can be rescued by manipulation of the mTOR pathway. The results from this study will reveal key molecular events that participate in spatial memory by investigating the activity and role of the TSC-mTOR pathway in the hippocampus. The results from these studies will provide a crucial step towards development of pharmacological and/or molecular strategies to treat memory disorders.